Before The Ink Was Dry: A 3D Bioprinting Forecast

The pitfalls and victories of current 3D Bioprinting companies underscore the importance of multidisciplinary approaches in Biotech. Those who enter the field must master the trapeze act of balancing economic sustainability and disruptive innovation while juggling regulatory and reimbursement hurdles.

Summary

The success of a biotech startup heavily relies on the use case. In most entrepreneurial endeavors, the use case mainly involves consumer interest. For health applications, this becomes more complicated once we consider reimbursement and regulatory concerns.

As far as 3D printing goes, many would agree (at least the sci-fi fans) that the most exciting use case is bioprinted organs. 3D bioprinting typically involves a synthetic scaffold populated with living cells. We may be familiar with synthetic material used in transplants; perhaps a knee replacement device comes to mind. This would lead some to believe 3D bioprinted organs could be considered a medical device. On the other hand, the device is populated with cells — often stem cells. Now, you may argue the product is in fact a biologic. The organ would also interact with the body and participate in biochemical reactions within the body. So, would we apply for Premarket Approval (PMA) for a medical device or as a Investigational New Drug (IND)?

There is currently no 3D bioprinted soft tissue organ approved by the FDA for clinical use. There are, however, approved clinical uses for 3D bioprinted skeletal tissue. Companies like Osteopore and OssDsign have FDA approved products obtained by filing their products as medical devices and proving substantial equivalence to previously approved implants. The highly precarious regulatory landscape poses immense risk for any company attempting to enter the soft tissue market. Organovo is the brave contender to do just that. Recently, the company submitted an IND for their 3D bioprinted liver therapeutic tissue and await a response. If the IND is approved, this could accelerate Organovo’s growth and establish them as a world leader in synthetic soft tissue transplantations. Otherwise, the company may have to restructure their use case to stay afloat.

When a solution relies on technological advancement, waiting can be detrimental. At the core of every biotech and biopharma company is their research and development (R&D) department. It is through well funded R&D that these companies can produce high quality, disruptive technology. FDA applications can not only be a waiting game, but also an expensive investment. Timing is key. With such a novel area like bioprinting, does the current technology offer sufficient efficacy for therapeutic use? Is the regulatory pathways too vague? Is there an opportunity within 3D bioprinting to accumulate funds for R&D while strategizing an approach for clinical applications?

CELLINK has taken an interesting approach to 3D bioprinting soft tissues. Rather than focusing on the excitement around bioprinted organ transplants for clinical use, the company has targeted a practical market, research. With this approach, they were able to enter the consumer market immediately; collecting revenues without having to obtain FDA approval. It is already evident through the quality of their offerings that they have diversified their product lines and created solutions to many common issues. They have also created partnerships with multiple pharmaceutical and academic institutions to conduct soft tissues replacement research. With their superior product line and established partnerships, they can easily expand into soft tissue transplant when the timing is right.

This case illustrates how, often, biotech entrepreneurs get caught up in hype. Bringing sci-fi fantasies to reality may spark passion and initial investor interest, but long haul success is built on practical first steps.

Introduction

3D printing technology can be applied to a multitude of medical applications from creating patient-specific plastic models for those with visual impairments[1] to rapid-release drug tablets[2]. Bioprinting not only involves capable printers but also specific materials to dispense and build scaffolds; these materials are referred to a bio-inks[3]. New techniques and applications are constantly emerging within this novel area. This creates an enticing environment for investment and exploration in the biotechnology sector but also poses major market penetration challenges.

“ Global 3D Bioprinting Market is projected to reach
2,494.62 million USD at a CAGR of 20.34% by 2025 ”

— Market Research Future Report 2021 [4]

Strengths and weaknesses are heavily dependent on the company’s ability to retain revenue through market differentiation and product demand. Opportunities arise as the technology advances and manufacturers tap into underserved or emerging markets; and threats heavily rely on regulatory barriers but can also include ethical concerns and key competitors.

Bioprinting appears to challenge these determinants the greatly due to ambiguous regulatory environments and rapidly evolving techniques. Bioprinting technologies describe 3D printed structures that incorporate living cells, growth factors, and/or biomaterials.

This report will outline three themes of applications for this technology of which are:
(1) skeletal tissue repair,
(2) clinical trial application, and
(3) soft tissue replacement.

Skeletal Tissue Repair

Prior to 3D bioprinting capabilities, bone voids and other skeletal damages were mainly treated via bone autografts[5]. This process requires retrieving bone material from another part of the patient’s body to the damaged area accompanied by stem cells. The procedure is greatly limited by the size of the damaged area [6, 7] and this creates an underserved market. There is also increased risk associated with surgery, including infection and morbidity, due to multiple surgical sites [8].

Bioprinting methods mitigate many of these issues and many are interested in exploring effective bio-ink material. Often, compact bone structures are mimicked by ceramic scaffolds from calcium phosphate bio-inks [9]. Discovery of other bio-inks can enhance certain features and specialize application use. For example, polymers such as hydroxyapatite have shown to provide increased flexibility for bone tissue transplants in the spine [10].

Regulatory Considerations

Currently, approved technology [11, 12] in this category are considered medical devices and is therefore regulated by FDA’s Center for Devices and Radiological Health. Pathway options comprise of either Pre-Market Approval (PMA), a lengthy process involving multiple clinical trials for new devices, or the 510K process for device showing substantial equivalence to an already approved device [13].

Industry Prospect — Osteopore

Founded: 2003 — Singapore
Technology: 3D printed bioresorbable scaffolds for neurosurgical, orthopedic, and maxillofacial surgery use.

Osteopore supplies two main products; (1) the Osteoplug, a porous interconnected scaffold easily incorporated alongside living cells for use in neurosurgical burr holes and (2) the Osteomesh, a flexible but rigid matrix to fill craniofacial defects from surgery.

Both matrices can be reabsorbed and eventually replaced by the patient’s own bone. The polycaprolactone bio-ink utilized by the company is an FDA-approved polymer that allows for highly flexible yet mechanically strong scaffolding. The device has received FDA clearance, TGA clearance, and CE marking of conformity. FDA clearance was obtained via 510K as a class II device [11].

Notable Events:
· 2021 — Cooperation Agreement with Terumo Blood and Cell Technologies. The company’s products can be used to populate Osteopore’s scaffolds with the required living cells. The two will sell and promote the complementary products in conjunction with one another. This cooperation will allow Osteopore to take advantage of Terumo Blood and Cell Technologies’ extensive partner network in Asia-Pacific.
· 2012 — FDA recall due to suspected compromise in product sterility.

Company Aspirations:
· Plans to expand market penetration efforts into US and Europe.
· Explore further diversification of product lines into new therapeutic segments in dental and orthopedic that will likely undergo 510K.
· Future desire to explore new polymers and new tissue applications

Industry Prospect — OssDsign

Founded: 2011 — Sweden
Technology: 3D printed titanium scaffold for bone replacement

OssDsign developed a novel ceramic material combined with titanium scaffold for bone regeneration in cranioplasty and facial reconstructive surgery. The designs are patient-specific based on CT scans.

A clinical study of 50 patients yielded positive results despite a complex population where 64% of patients underwent prior removal of conventional implants [14].

In 2019, a global post-market follow-up with 670 patients yielded a low implant removal rate of 2% [15]. The company obtained FDA clearance via 510K based on KLS Martin — Patient Contoured Mesh as a substantially equivalent predicate [12].

Notable Events:
· 2019 — OssDsign received a nationwide contract with UK National Health Service in England.
· 2019 — Obtained 510K clearance to market accessories for their current products to expand clinical use of OssDsign’s cranial products.

Company Aspirations:
· Currently in discussion with Japan on reimbursement access to further expand portfolio of nationwide reimbursement and contracts.
· Strong focus on market expansion in new geographical regions.

Clinical Trial Applications

Clinical trials are known to attribute to high consumption of time and resources with notoriously steep failure rates. 3D modeling may imitate cellular interactions and tissue microenvironments which supports some prediction for future trials [16]. Not only does this provide improved project workflow, but 3D bioprinted models for clinical trials can also create opportunities to explore relevant biomarkers. A 2018 study [17] utilized a 3D bioprinted brain tumor model to verify a tumor angiogenesis biomarker and assess drug susceptibility in vitro. In many aspects, this technology poses a great attraction to the academic and pharmaceutical industries.

Regulatory Considerations

This category describes companies that offer bio-inks and bioprinters that are not intended to only be distributed to academic and pharmaceutical labs for scientific exploration. Therefore, prospective manufacturers are only required to file regulatory documents for conducting business within the US and internationally [18]. Many of the compounds used as their bio-inks are FDA approved from the Center for Drug Evaluation and Research (CDER) prior to marketing but it is not necessary.

Industry Prospect — CELLINK

Founded: 2016 — Sweden
Technology: Light-based and extrusion bioprinters and bio-inks for research models

CELLINK provides versatile solutions for a range of research projects via precise modular temperature-controlled printers for different bio-inks. With over 40 bio-inks, CELLINK owns the largest portfolio of tissue-specific bio-inks that are universally compatible with any 3D-bioprinting platform [18]. They also obtained a patent for their Clean Chamber technology in all their 3D bioprinters which include both UV sterilization and HEPA filtration.

In addition to their extrusion bioprinters, they also carry unique light-based bioprinters that distribute more consistent printing with higher resolution for more intricate, accurate designs. The light cures the bio-ink rapidly to reduce the distortion and wait times for hydrogels seen in other 3D bioprinters.

A major success story of the company comes from Florida Agriculture and Mechanical University. A lab group in the Pharmacy department developed the first human cornea in the US used to test relief and treatment therapies using CELLINK’s BIO X bioprinter [19].

CELLINK along with its subsidiaries have successfully integrated their platform into majority of the world’s 25 largest pharmaceutical companies.

Notable Events:
· 2019 — Acquired Cytena GmbH, a single-cell printing company in anticipation of further product expansion. The complementary technology of CELLINK’s bioprinting platform with antibodies and cell lines will contribute to a more attuned environment.
· 2019 — Acquired Dispendix GmbH, which has developed a bio-dispensing technology to accelerate drug development and other biological research workflows. This will further attract partnerships within the pharmaceutical industry.

Company Aspirations:
· CELLINK is currently focused on product development and diversification.
· Commitment to research and continuous innovation drives their goal to increase the number of partnerships with academia and especially pharma.

Soft Tissue Replacement

A major issue of this theme is distortion of soft and liquid bio-inks due to gravity [20, 21]. This application requires very flexible bio-inks such as a hydrogel. To mitigate this issue as much as possible, rapid curing or suspension of the model in a liquid is necessary [21]. A recent major advancement was made in 2020 when a group of scientists successfully 3D bioprinted a fully functional human heart using the Freeform Reversible Embedding of Suspended Hydrogels (FRESH) technique to limit distortion [20]. Despite extraordinary milestones such as this in research, clinical use of these technologies is scarce — mainly due to major regulatory hurdles.

Regulatory Considerations

Soft tissue replacement is one of the most ambiguous and precarious themes for 3D bioprinting regulation. Arguably, current regulatory frameworks of drugs, biologics, or devices are not comparable to synthetic tissue or organ. A 3D bioprinted organ is different than a transplant from another human donor or autography, a process where the patient’s own tissue is manipulated [22]. Since it consists of synthetic material as well as biological material, the classification of this product is extremely challenging. One could argue the synthetic component, or the scaffold, holds similarities to a medical device. In this case, the technology may be submitted as a medical device via the lengthy, time-consuming, and costly PMA pathway. Another may position this product as a biologic since the synthetic scaffolds are coated with proteins and living cells — often stem cells.

Currently, human cells and tissue intended for transplant are regulated by Center for Biologics Evaluation and Research (CBER) under the Code of Federal Regulations Title 21 Parts 1270 and 1271 which identifies donor eligibility and current good tissue practices [23]. However, this does not include vascularized human organ transplants such as the liver, heart, or kidneys. In these cases, the health Resources Service Administration (HRSA) is the corresponding FDA center. Yet others may disagree with all the above and classify these products as a drug, based on their medical indication and ability to participate in chemical reactions within the body. This would require an Investigational New Drug (IND) application with the FDA.

A prospective company in this field would have to be extremely strategic with their respective FDA application and understand how to best position their product. The FDA released a guidance document for 3D printed products in 2017 which outlines technical information that should be included in submissions to assist in this ambiguous regulatory area in an attempt to face the precarious milieu.

Industry Prospect — Organovo Holdings Inc.

Founded: 2007 — United States
Technology: ExVive™ 3D Bioprinted Human Liver Tissue for clinical use; NovoGen Bioprinter® Platform for drug discovery.

Organovo develops in vivo liver tissues with a focus on orphan diseases with organ transplant being one of the limited treatment options.

The two main products they provide are:
· ExVive 3D Bioprinted Human Liver Tissue;
· NovoGen Bioprinter® Platform that can create a spectrum of tissues: healthy liver, NASH liver, kidney, intestine, skin, vascular, bone, skeletal muscle, eye, breast and pancreatic tumor.

In addition to these main products, Organovo aims to create therapeutic tissue referred to as NovoTissues while also producing models for drug profiling. Their 3D toolkits allow for biomarker analysis by identifying disease clusters with genetic markers.

Notable Events:
· 2016 — Acquired Samsara Sciences, a company devoted to the provision of high-quality primary human liver and kidney cells. The research areas of these two companies align well and the products are compatible.
· 2017 — First regulatory milestone of obtaining orphan designation for their first indication. This marks the beginning of their intended trajectory towards building IND-track therapeutics.

Company Aspirations:
· They plan to enter a new therapeutic area of Crohn’s Disease and Ulcerative Colitis among other Inflammatory Bowel Diseases since they have successfully established a 3D bioprinted intestinal model [24].
· Organovo has submitted their first IND application to the FDA in 2020 and awaits a response. The company hopes this will be just the first of many INDs.

Conclusion

From this analysis, of the 3 themes, the clinical trial application appears to be the most volatile for growth short-term. The other two have the potential to one day succeed over the clinical trial application, but that transition could only take place in the distant future.

This sets CELLINK to be considered the best-of-class in comparison to the four 3D bioprinting companies assessed in this report. The company was able to enter the market immediately and start collecting revenues early by targeting academic and pharmaceutical sectors. As a company with a devotion to research, they themselves are constantly exploring their products and redeveloping according to application needs. In September 2019, the company launched their upgraded BIO X printer, the BIO X6, that includes 6 coaxial printheads for increase biofabrication modalities. This commitment in leading edge technologies and continuous innovation will be a key strength for future growth of CELLINK.

Their market strategy allows them to develop credibility and grow their specialization in 3D bioprinting. It is already evident through the quality of their products that they have diversified their product lines and created solutions to many common issues. For instance, the issue with many 3D bioprinted products is sterility; this becomes a major concern especially when the product may be transplanted into patients. This issue was seen with Osteopore when their products were recalled in 2012 due to sterility concerns. This is extremely relevant as the main concern these companies monitor in clinical and post market studies is infection rates. CELLINK exemplifies leading-edge thinking through their patented Clean Chamber technology in this regard. Furthermore, the company may have also mitigated distortion of hydrogel bio-inks seen in many soft tissue models by developing light-based bioprinters. Their expertise can enable them to later expand into soft tissue transplant alongside their multiple research partners.

Contrary to this, Organovo has taken the opposite approach by starting with tissue transplant models where major regulatory barriers exist, then opening into the research market as a supplier of 3D bioprinted models. The company has seen huge growth in its early stages and received a lot of investment attraction in the past, but regulatory hurdles and choice of market may lead to its downfall. The company was not focused on gaining sales and retaining positive revenue growth, which effectively hindered their opportunities to innovate and further develop their products. Now, as the company awaits response from the FDA on their IND, there is a lot of uncertainty with where the company is headed. If the IND is approved, this could accelerate Organovo’s growth and establish them as a world leader in synthetic soft tissue transplantations. Otherwise, the company will have to reframe their strategy and focus on market development in the research sector while competing with companies like CELLINK.

The current niche market segments have allowed Osteopore to grow without aggressive competition for the time being. The company has managed to strategize their regulatory applications with little resistance. Their recent Cooperation Agreement with Terumo Blood and Cell Technologies poses a great incentive for investment as this reflects deepening of their current Asia-Pacific markets. However, their FDA recall may make some investors hesitant over the company.

Finally, OssDsign’s established a stable European growth and is starting to expand into the US. There is quite a bit of growth potential as the company further expands geographically and continues to achieve nationwide reimbursement contracts. The company’s superior technology differentiates them from competitors and regulatory is not a concern at this time. Overall, the company appears to be a positive investment, but not extremely volatile in comparison to CELLINK.

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